a. Field of Invention
Isomers of 1-azabicyclo[2.2.2]oct-3-yl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylat and their nontoxic acid addition salts are useful calcium antagonists having utility as antihypertensive agents, as peripheral and cerebral vasodilators and as coronary therapeutic agents.
b. State of the Art
Before the turn of the century some workers postulated that Ca.sup.++ played a role in the process of muscle contraction. However it was not until 1965, with the discovery of troponin, a Ca.sup.++ binding protein, that the role of Ca.sup.++ in the process of muscle contraction was defined. Soon thereafter it was demonstrated that papaverine, an opium alkaloid, and other structurally related compounds known to dilate coronary blood vessels exerted their spasmolytic effect by a Ca.sup.++ channel antagonist mechanism. This directly led to the development of antagonist drugs. Specifically, it was found that 4-aryldihydropyridines were potent Ca.sup.++ channel blockers. Nifedipine, dimethyl 1,4-dihydro-2,6-dimethyl4-(2-nitrophenyl)-3,5-pyridinedicarboxylate, is the prototype of such therapeutic agents.
1,4-Dihydropyridines function by slowing the entry of Ca.sup.++ ions into cells, thereby reducing the force of muscle contraction. Typically, they produce vasodilatation of the peripheral vasculature, especially that of the arteries, to cause a reduction of blood pressure. Clinical applications are particularly directed toward the treatment of oxygen deficiencies of the heart such as angina pectoris and hypertension.
The effects of stereochemistry on the biological actions of this class of pharmacological agent have been studied. For example, the conformation of the dihydropyridine ring, in particular its degree of planarity (R. Fossheim, A. Joslyn, A. J. Solo, E. Luchowski, A. Rutledge, and D.J. Triggle, J. Med Chem., 1988, 31, 300), has been related to potency. Furthermore, when the 3 and 5 ester groups are unsymmetrically substituted, the actions of opposite enantiomers or diastereomers can vary significantly. For example (R. P. Hof, A. Hof, U. T. Ruegg, N. S. Cook, and A. Vogel, J. Cardiovascular Pharmacol., 1986, 8, 221.), the (R)-enantiomer of isopropyl methyl 4-(2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (PN 200-110) had almost no effect on heart rate and blood pressure, although it was surprisingly potent in the subendocardium of the left ventricle. On the other hand, the (S)-enantiomer lowered blood pressure and heart rate, whereas both (R)- and (S)-enantiomers increased cardiac output and blood flow to the heart and brain. These results suggest that Ca.sup.++ channels are able to discriminate between enantiomers and also respond to them differently.
Attempts to increase both potency and clinical selectivity have led to the incorporation of a second center of symmetry into the 1,4-dihydropyridine nucleus wherein one ester moiety is both chiral and basic. For example G. Marciniak, A. Delgado, G. Leclerc, J. Velly, N. Decker and J. Schwartz, (J. Med. Chem., 1989, 32, 2504.) incorporated a mimic of the known alpha blocker prazosin, into an ester function to give all four enantiomers of the diastereomeric pairs of 2-[N-methyl-N-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl] amino]ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylat e. The (R,R)-enantiomer was the most potent inhibitor of [3H]- nitrendipine binding, whereas the (S,S)-enantiomer was the most potent inhibitor of [3H]-yohimbine binding.
The preparation of the individual enantiomers of the diastereomeric 1-benzyl-3-pyrrolidinyl (K. Tamazawa, H. Arima, T. Kojima, Y. Isomura, M. Okada, S. Fujita, T, Furuya, T. Takenaka, O. Inagaki, and M. Terai, J. Med Chem., 1986, 29, 2504. U.S. Pat. No. 4,220,649) and 1-benzyl-3-piperidinyl (K. Muto, T. Kuroda, H. Kawato, A. Karasawa, K. Kubo, and N. Nakamizo, Arzneim.-Forsch./Drug Res. 1988, 38, 1662, U.S. Pat. No. 4,501,748) esters of methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate have been reported. Both groups reported that the (S,S)- enantiomer exerted the greatest Ca.sup.++ channel blocking activity as determined by inhibition of [3H]-nitrendipine binding and by lowering of blood pressure in spontaneously hypertensive rats respectively.
The novel isomers of 1-azabicyclo[2.2.2]oct-3-yl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate described herein are potent calcium channel antagonists as evidenced by their ability to inhibit Ca.sup.++ evoked contractions of guinea pig ileum and by their ability to inhibit [3H]-nitrendipine binding. Moreover, it was unexpected that the pharmacological action would be influenced by the bicyclic ester radical to such an extent that the C4 (R) configuration was favored. This was in direct contrast to the generally held belief that the C4 (S) configuration was most active (U.S. Pat. No. 4,761,420) and to analogous diastereomeric dihydropyridines with an asymmetric carbinol carbon in a cyclic amine ester radical, in which the C4 (S) configuration was also most potent (U.S. Pat. Nos. 4,220,649 and 4,501,748).